Alterations in the CSB gene in three Italian patients with the severe formof Cockayne syndrome (CS) but without clinical photosensitivity

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by postnatal growth failure, mental retardation and otherwise clinically h eterogeneous features which commonly include cutaneous photosensitivity. Cu ltured cells from sun-sensitive CS patients are hypersensitive to ultraviol et (UV) light and, following UV irradiation, are unable to restore RNA synt hesis rates to normal levels. This has been attributed to a specific defici ency in CS cells in the ability to carry out preferential repair of damage in actively transcribed regions of DNA. We report here a cellular and molec ular analysis of th ree Italian CS patients who were of particular interest because none of them was sun-sensitive, despite showing most of the featur es of the severe form of CS, including the characteristic cellular sensitiv ity to UV irradiation, They all were altered in the CSB gene. The genetical ly related patients CS1PV and CS3PV were homozygous for the C1436T transiti on resulting in the change Arg453opal. Patient CS2PV was a compound heteroz ygote for two new causative mutations, insertions of an A at position 1051 and of TGTC at 2053, leading to truncated proteins of 367 and 681 amino aci ds. These mutations result in severely truncated proteins, as do many of th ose that we previously identified in several sun-sensitive CS-B patients. T hese observations confirm that the CSB gene is not essential for viability and cell proliferation, an important issue to be considered in any speculat ion on the recently proposed additional function of the CSB protein in tran scription. Our investigations provide data supporting the notion that other factors, besides the site of the mutation, influence the type and severity of the CS clinical features.